Signaling through the epidermal growth factor receptor (EGFR) is important in colonic epithelial homeostasis and disease. Therefore, finding new methods to modulate EGFR signaling could have significant therapeutic application toward the treatment of gastrointestinal diseases. Targeted epigenetic modulation represents a novel method to regulate cell responses to EGFR signaling. Preliminary data from our lab including an unbiased epigenetic shRNA screen, demonstrated that the nuclear scaffold protein menin and its histone methyltransferase binding partner mixed lineage leukemia (MLL) are critical for cell survival in the setting of EGFR inhibition. There is no known connection between menin/MLL and EGFR signaling reported in the literature, leading us to our hypothesis that the menin/MLL axis serves as an important epigenetic mechanism that enables colonic epithelial-derived cells including colon cancer cells to survive when EGFR signaling is inhibited. This hypothesis will be pursued in two interrelated Specific Aims: (1) Define the mechanism of menin/MLL mediated cell survival in the setting of EGFR inhibition. (2) Determine if menin/MLL is important for cell survival during EGFR inhibition in vivo. This proposal will utilize both in vitro and in vivo approaches to define the crosstalk between the menin/MLL and EGFR signaling pathways that is crucial for menin/MLL mediated cell survival in the setting of EGFR inhibition. The experiments in this innovative proposal will also have direct application toward the development of novel therapies for the treatment of both benign and malignant colorectal diseases, including inflammatory bowel disease and colon cancer. In addition, this research proposal will be supported in an integrated manner through exceptional mentorship, an already constituted research advisory committee, and unequivocal divisional and institutional commitment. Finally, this K08 award will serve as a basis for the ultimate achievement of my career goal to become an independent physician-scientist at a major academic medical center.